The long term objective of the proposed research is to develop new antineoplastic agents using nybomycin acetate as the "lead" compound. Nybomycin acetate (1b), a polyfunctional tetracyclic natural product, is an important "lead" structure because it possesses broad-spectrum activity against a range of leukemias and solid tumors. The compound did not go into human trials because it was very insoluble and also, in part, because of the moderate level of the antitumor activity. The specific aims of this project are to design, synthesize and evaluate nybomycin acetate congeners that are sufficiently soluble and stable for drug formulation, that possess activity against the more intractable solid neoplasias and show a higher level of activity than nybomycin acetate. The project also proposes to evaluate those structural factors that contribute to antineoplastic activity and those that contribute to toxicity in an effort to achieve the most favorable therapeutic index. The development of nybomycin acetate congeners follows two courses. The first is based on the possibility that nybomycin acetate functions as an electrophilic agent and the second on the possibility that nybomycin acetate functions in an analogous manner to the anthracycline drugs. In both cases two additional factors are given attention. These are the need for water solubilizing moieties (either as "permanent" drug modifications or prodrug modifications) and the possibility of metabolic activation. The proposed chemical approach uses an economy of chemical methods and intermediates. Proven methods that have been used to prepare simpler nybomycin congeners are used to prepare more complex compounds and the synthesis of several different compounds are designed to use the same key intermediate. The key elements in the syntheses are first the elaboration of hexasubstituted benzenes with the subsequent cyclization to the 1,9-diazaanthracene and, second, the functional group transformations on the 1,9-diazaanthracene.